Johns Hopkins researchers have discovered that many
people with Bardet-Biedl syndrome, a rare, complex
condition marked by an array of seemingly unconnected
symptoms, including obesity, learning difficulties, eye
problems and asthma, also have another, previously
unreported problem: Many of them can't detect odors.

Because people with the syndrome likely lose their
sense of smell before or shortly after birth, it wouldn't
occur to them to mention it, and so the problem, known as
anosmia, had never been reported, the researchers say.

But spurred by new understanding that the problems
seen in BBS are caused by faulty cellular structures called
cilia, researchers led by Nicholas Katsanis decided to look
into patients' ability to detect odors. The olfactory
system, which is responsible for the sense of smell, is
perhaps the most cilia-rich system in the body, relying on
a bed of the tentaclelike structures to detect odiferous
molecules as they pass through the nose.

Sure enough, when colleagues at University College
London administered a simple standard smell test to BBS
patients, 40 percent couldn't smell anything, and another
10 percent had a reduced odor-detecting ability. The Johns
Hopkins researchers then turned to mice missing either of
two BBS-causing genes to prove that faulty cilia, rather
than any other problems, were to blame. The results are
described in the Aug. 22 advance online section of Nature
Genetics.

"This proves beyond a shadow of doubt that the
mechanism we've proposed--faulty cilia--is behind the
syndrome," says Katsanis, an assistant professor in
Hopkins'
McKusick-Nathans Institute of Genetic
Medicine. "Without the mouse studies, the problem could
have been at any step along the way, from detecting odors
to communicating with the brain to pulling up the right
word to describe the odor.

"But we've proven that loss of the BBS proteins causes
ciliary problems in mice, and the ciliary problems cause
the clinical symptom," he says. "I love it when science
makes sense."

Last year, Katsanis and an international team of
colleagues discovered that BBS-involved proteins were found
in and near cilia, and they suggested that faulty cilia
might explain the variable problems in BBS. But until now,
there was no direct proof that the ciliary problems they'd
observed in worms and cells were also present in mice or
people with BBS-causing genetic mutations.

"We took a disease associated with cilia and looked at
a system whose whole job, its raison d'etre, essentially is
making cilia," says Randall Reed, a professor of
molecular biology and
genetics in Hopkins' Institute for Basic Biomedical
Sciences and a Howard Hughes Medical Institute
investigator. "If the association was right, we'd expect an
effect."

Heather Kulaga and Carmen Leitch, Reed's and Katsanis'
research assistants, respectively, studied mice missing
either of two BBS-causing genes, BBS1 or BBS4, to figure
out whether the animals' sense of smell was impaired. (All
four of the patients who had mutations in BBS4 were unable
to smell.)

The overall organization of the olfactory system in
both sets of mice seemed normal, they discovered, but
instead of the normal sea-grass-like patch of lengthy cilia
where smelly molecules usually come to rest, the mice had
only short, stumpy cilia wannabes. The stunted cilia
couldn't detect odor-causing molecules, so virtually no
electrical signals were sent to the brain, Kulaga
discovered in experiments where she measured the electrical
signals, or lack thereof.

"These animals don't have structures for detecting
odors," says Reed, who has been studying the cellular
proteins involved in detecting odors for close to 20 years.
"The cilia were dramatically deformed, and key
odor-detecting proteins weren't where they should have been
but were trapped in different places in the cell."

Kulaga also found fewer of these key odor-detecting
proteins in the knockout mice than in normal mice. The
researchers still need to figure out why but suggest there
may be a feedback loop that keeps expression low because
odors aren't being detected or because, once made, the
proteins aren't moved to their proper locations.

Katsanis and Reed both say they are excited about
their "perfect" collaboration--Katsanis because the
olfactory system is a great model to figure out the details
of how BBS-causing mutations upset ciliary function, and
Reed because the BBS genes and proteins are a whole new
toolbox to probe the nose.

"We knew a lot about what these olfactory neurons look
like but really very little about how they got that way,"
Reed says. "Now we have a whole collection of genes, the
BBS genes, to use to see how the cells' long cilia are made
and how they work."

The research was funded by the National Institute of
Child Health and Development, the National Institute for
Deafness and Other Communication Disorders, the National
Institutes of Health, the March of Dimes, the Howard Hughes
Medical Institute, the National Kidney Research Fund and
the Wellcome Trust.

Authors on the paper are Kulaga, Leitch, Reed,
Katsanis, Jose Badano and Alysa Lesemann, all of Johns
Hopkins; Erica Eichers and James Lupski, of Baylor College
of Medicine; and Bethan Hoskins and Philip Beales, of
University College London.